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Malaria
claims a million lives a year, a majority of which are children, and threatens
the lives of billions more within its tropical ranges. It is caused by Plasmodium, a parasite that uses mosquitoes as a way of
getting in to and out of humans. Initial
infection from the bite of a carrier mosquito is followed by the parasite’s
massive proliferation and colonisation of the host’s blood, causing a suite of debilitating
symptoms and providing a parasitized food source for the next mosquito. In the
absence of a vaccine, prevention and treatment remain our only effective
weapons against malaria. Today, the most effective treatment regime relies
heavily on artemisinin, a compound from an Asian herb that effectively targets
the parasite within red blood cells. But, as was the case for previous
anti-malarial drugs, the spectre of artemisinin-resistant Plasmodium strains is rising. Worryingly, as there is currently no
clear fall back to artemisinin, a global spread of resistance will seriously
harm our ability to tackle the disease.
claims a million lives a year, a majority of which are children, and threatens
the lives of billions more within its tropical ranges. It is caused by Plasmodium, a parasite that uses mosquitoes as a way of
getting in to and out of humans. Initial
infection from the bite of a carrier mosquito is followed by the parasite’s
massive proliferation and colonisation of the host’s blood, causing a suite of debilitating
symptoms and providing a parasitized food source for the next mosquito. In the
absence of a vaccine, prevention and treatment remain our only effective
weapons against malaria. Today, the most effective treatment regime relies
heavily on artemisinin, a compound from an Asian herb that effectively targets
the parasite within red blood cells. But, as was the case for previous
anti-malarial drugs, the spectre of artemisinin-resistant Plasmodium strains is rising. Worryingly, as there is currently no
clear fall back to artemisinin, a global spread of resistance will seriously
harm our ability to tackle the disease.
The
research of Miotto, et al. was stimulated by the observation that resistance to
artemisinin, and indeed some of its forebear drugs, appears to originate in the
same part of the world: the remote mountains of western Cambodia. To tackle the
question of why drug resistance originates here, the researchers sought clues
within the parasite’s genome. They had previously developed a technique to
isolate Plasmodium DNA directly from
the blood of infected patients: a blood sample is taken, white blood cells
removed (this removes a lot of the human DNA content which can complicate
analysis), and DNA extracted and sequenced
using modern sequencing technology. For this work they do not require the parasite
genome sequenced in its entirety; rather, they seek sufficient coverage to
allow reliable identification of variability between samples.
research of Miotto, et al. was stimulated by the observation that resistance to
artemisinin, and indeed some of its forebear drugs, appears to originate in the
same part of the world: the remote mountains of western Cambodia. To tackle the
question of why drug resistance originates here, the researchers sought clues
within the parasite’s genome. They had previously developed a technique to
isolate Plasmodium DNA directly from
the blood of infected patients: a blood sample is taken, white blood cells
removed (this removes a lot of the human DNA content which can complicate
analysis), and DNA extracted and sequenced
using modern sequencing technology. For this work they do not require the parasite
genome sequenced in its entirety; rather, they seek sufficient coverage to
allow reliable identification of variability between samples.
The
researchers collected samples from infected patients in west Africa and southeast
Asia, including four sites in Cambodia, one in the east and three in the west. A
global survey of the genetic data revealed that the Asian and African
populations have distinct patterns of genetic variation, consistent with their
geographical isolation. Within the Asian sample, the story was a little more
complex. Samples from western Cambodia were notably distinct from those in eastern
Cambodia and Thailand. The western Cambodian populations were also
‘structured’, that is, the population was split into subpopulations, each with
their own distinct genetic signatures. The subpopulations were also relatively
inbred, lacking in genetic diversity, which is often a signature of a recent
expansion from a small, homogenous population. Crucially, the researchers were
able to show that the subpopulations that predominate in western Cambodia showed
artemisinin resistance, as infected patients responded poorly to treatment.
Thus, while the distinct subpopulations of Plasmodium
in western Cambodia are genetically distinct, they present the same problem:
artemisinin resistance.
researchers collected samples from infected patients in west Africa and southeast
Asia, including four sites in Cambodia, one in the east and three in the west. A
global survey of the genetic data revealed that the Asian and African
populations have distinct patterns of genetic variation, consistent with their
geographical isolation. Within the Asian sample, the story was a little more
complex. Samples from western Cambodia were notably distinct from those in eastern
Cambodia and Thailand. The western Cambodian populations were also
‘structured’, that is, the population was split into subpopulations, each with
their own distinct genetic signatures. The subpopulations were also relatively
inbred, lacking in genetic diversity, which is often a signature of a recent
expansion from a small, homogenous population. Crucially, the researchers were
able to show that the subpopulations that predominate in western Cambodia showed
artemisinin resistance, as infected patients responded poorly to treatment.
Thus, while the distinct subpopulations of Plasmodium
in western Cambodia are genetically distinct, they present the same problem:
artemisinin resistance.
Image Source: Shutterstock Copyright: GuoZhongHua
The
beauty of these kinds of genomic studies is that as well as just looking at the
variation between groups accross the genome, on a global scale, we can zoom in
and focus on the individually varying regions to ask whether these parts do
anything relevant. The researchers made the important observation that the western
Cambodian subpopulations harbour a number of genetic changes associated with
drug resistance, including alterations to genes which control the entrance of
molecules into the cell. One of the subpopulations even harboured mutations in
genes involved in preventing mutations, raising the intriguing possibility that
a general increase in mutability of the genome may provide more drug resistance
mutations.
beauty of these kinds of genomic studies is that as well as just looking at the
variation between groups accross the genome, on a global scale, we can zoom in
and focus on the individually varying regions to ask whether these parts do
anything relevant. The researchers made the important observation that the western
Cambodian subpopulations harbour a number of genetic changes associated with
drug resistance, including alterations to genes which control the entrance of
molecules into the cell. One of the subpopulations even harboured mutations in
genes involved in preventing mutations, raising the intriguing possibility that
a general increase in mutability of the genome may provide more drug resistance
mutations.
Identifying
the source of emerging drug resistance, both in terms of geography and
underlying genetic causation, is a critical task if we are to control its
spread. Hence the importance of this work for malaria control. The fact that
there are multiple, independent artemisinin-resistant subpopulations shows that
there are many routes for a parasite to become resistant. In practical terms the
genetic signatures within the resistant strains can be used as biomarkers for
artemisinin resistance in any sample of Plasmodium
DNA, allowing health authorities to monitor its spread. Furthermore these
genetic signatures will add to our biological understanding of how the
parasites evolve to resist the drug.
the source of emerging drug resistance, both in terms of geography and
underlying genetic causation, is a critical task if we are to control its
spread. Hence the importance of this work for malaria control. The fact that
there are multiple, independent artemisinin-resistant subpopulations shows that
there are many routes for a parasite to become resistant. In practical terms the
genetic signatures within the resistant strains can be used as biomarkers for
artemisinin resistance in any sample of Plasmodium
DNA, allowing health authorities to monitor its spread. Furthermore these
genetic signatures will add to our biological understanding of how the
parasites evolve to resist the drug.
We
are still however left with our opening question: why Cambodia, specifically
why Western Cambodia? The authors propose a number of potential contributory
factors, including the potential higher mutation rate, heavy use of drugs and
local isolation of the populations (favouring inbreeding) due to the remoteness
of the region. General features of host-parasite interactions are thus married
with particularities of the region to provide a potent reservoir of drug
resistance. Whatever the underlying causes, the next imminent step will be
containment of these variants to prevent their global spread.
are still however left with our opening question: why Cambodia, specifically
why Western Cambodia? The authors propose a number of potential contributory
factors, including the potential higher mutation rate, heavy use of drugs and
local isolation of the populations (favouring inbreeding) due to the remoteness
of the region. General features of host-parasite interactions are thus married
with particularities of the region to provide a potent reservoir of drug
resistance. Whatever the underlying causes, the next imminent step will be
containment of these variants to prevent their global spread.
This summary by Aidan Maartens was shortlisted for Access to Understanding 2014 and was awarded third prize. It describes research published in the following article, selected for inclusion in the competition by the Wellcome Trust:
PMCID: PMC23624527
O. Miotto, J. Almagro-Garcia, M. Manske, B. MacInnis, S. Campino, K. A. Rockett, … D. P. Kwiatkowski.
Nature Genetics (2013) 45(6), 648-655.
Access to Understanding entrants are asked to write a plain English summary of a research article. For Access to Understanding 2014 there were 10 articles to choose from, selected by the Europe PMC funders. The articles are all available from Europe PMC, are free to read and download, and were supported by one or more of the Europe PMC funders.
Look out here and on Twitter @EuropePMC_news for further competition news and other Europe PMC announcements.
